ES2228066T3 - UREA DERIVATIVES FOR THE TREATMENT OF PAIN. - Google Patents

Abstract

A compound of formula I in which: m = n = 1 R1 is selected from (i) a linear or branched C1-C6 alkyl; and (ii) hydrogen; R2 is selected from (i) methyl; or (ii) phenyl optionally substituted with 1 or 2 substituents Y, in which Y is as defined below; R3 is selected from (i) -CH2-phenyl optionally substituted with 1 or 2 substituents Y, in which Y is as defined below; (ii) -CH2-cyclohexyl; R4 is selected from (i) hydrogen; or (ii) methyl; R5 is selected from (i) hydrogen; (ii) methyl; or (iii) or R4 and R5 together form a heterocyclic ring, optionally substituted with 1 or 2 Y substituents, in which Y is selected individually and independently from any of hydrogen, CH3, - (CH2) p1CF3, halogen, C1- alkoxy C3, hydroxy, -NO2, -OCF3, -CONRaRb, -COORa, - CORa, - (CH2) p2NRaRb, - (CH2) p3CH3, - (CH2) p5SO2Ra, (alkylcycloalkyl) C4-C8 in which alkyl has C1- C2 and the cycloalkyl is C3-C6 cycloalkyl; and in which Ra and Rb are individually and independently selected from hydrogen, a branched or linear C1-C6 alkyl, C1-C6 alkenyl, C3-C8 cycloalkyl, and in which p1, p2, p3, p4, p5 and p6 is each and independently 0, 1 or 2, as well as its pharmaceutically acceptable salts.

Description

Urea derivatives for the treatment of pain.

Field of the Invention

The present invention relates to new compounds, to a procedure for its preparation, to its use and to Pharmaceutical compositions comprising the new compounds. The new compounds are useful in therapy, and in particular for The treatment of pain.

Background and prior art

The δ receptor has been identified as having a role in many bodily functions such as systems circulatory and pain. Therefore, the ligands for the δ receptor can find a potential use as analgesics and / or as antihypertensive agents. The ligands for the  δ receptor have also shown that they possess activities immunomodulators

The identification of at least three populations different from opioid receptors (µ, δ and κ) It is now well recognized, and all three appear in the systems central and peripheral nervous of many species, including the man. Analgesia has been observed in various animal models when one or more of these receivers has been activated.

With a few exceptions, the delta ligands selective opioids, currently available, have nature peptide and are unsuitable for administration via routes systemic For some time some have been available non-peptide δ antagonists (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269, for a review). These compounds, for example naltrindole, have a rather bad selectivity (i.e. <10 times) by union to the δ receptor versus the γ receptor, and they do not show analgesic activity, a fact that emphasizes the need for development of highly non-peptide δ ligands selective.

In this way, the problem that underlies the present invention was to find new analgesics that had improved analgesic effects, but also had a profile improved side effects with respect to agonists µ current, and a potential oral efficacy.

The analgesics that have been identified and that exist in the prior art have many disadvantages in that they suffer from bad pharmacokinetics, and they are not pain relievers when they administered by systemic routes. Also, it has been documented that the preferred compounds, described in the prior art, show significant seizure effects when administered systemically

The problem mentioned above has been now resolved by developing new phenyl compounds 1,4-substituted, as will be described continuation.

The new compounds according to the present invention are defined by the general formula I

one

in the that:

m = n = 1

R1 is selected from

(i)

a linear or branched C 1 -C 6 alkyl; and

(ii)

hydrogen;

R2 is selected from

(i)

methyl; Y

(ii)

phenyl optionally substituted with 1 or 2 substituents Y, in which Y is as defined more down;

R3 is selected from

(i)

-CH2 -phenyl optionally substituted with 1 or 2 substituents Y, in which Y is as defined below; Y

(ii)

-CH2 -cyclohexyl;

R 4 is selected from

(i)

hydrogen; Y

(ii)

methyl;

R 5 is selected from

(i)

hydrogen;

(ii)

methyl; Y

(iii)

2

or

R 4 and R 5 together form a heterocyclic ring, optionally substituted with 1 or 2 substituents Y, and Y is selected individually and independently from any of hydrogen, CH 3, - (CH 2) p1 CF3, halogen, C1-C3 alkoxy, hydroxy,
-NO 2, -OCF 3, -CONR a R b, -COOR a, -COR a, - (CH 2) p2 NR a R b, - (CH 2) p 3 CH 3, - (CH 2) p 5 SO 2 R a, (alkylcycloalkyl) C 4 -C 8 in which alkyl has C 1 -C 2 and the cycloalkyl is C 3 -C 6 cycloalkyl;

R a and R b are selected individually and regardless of hydrogen, an alkyl C 1 -C 6 branched or linear, alkenyl C 1 -C 6, cycloalkyl C_ {3} -C_ {8}, and in which

p1, p2, p3, p4, p5 and p 6 is each and independently 0, 1 or 2, as well as their pharmaceutically acceptable salts.

By "halogen" is meant chlorine, Fluoro, bromine and iodine.

By "aryl" is meant a ring aromatic having 6 or 10 carbon atoms, such as phenyl and Naphthyl

By "heteroaryl" is meant a ring aromatic in which one or more of the 5-10 atoms in the ring are elements other than carbon, such as N, S and OR.

By "isomers" is meant compounds of the formula (I) that differ in the position of their functional group and / or orientation. By "orientation" is meant stereoisomers, diastereoisomers, regioisomers and enantiomers

By "isoforms" is meant compounds of the formula (I) that differ in the relative physical disposition of the molecules in the crystalline network, so that the isoforms are refer to various crystalline compounds and compounds amorphous

By "prodrug" is meant derivatives pharmacologically acceptable, for example esters and amides, of so that the product resulting from the biotransformation of the derivative is an active form of the drug. It is incorporated here as reference Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., MacGraw-Hill, Ed. Int. 1992, "Biotransformation of Drugs", p.13-15, which describes prodrugs in a general way.

The new compounds of the present invention they are useful in therapy, especially for the treatment of various pain states, such as chronic pain, acute pain, pain from cancer, pain caused by rheumatoid arthritis, migraine, pain visceral, etc. However, this list should not be interpreted as exhaustive

The compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as antitumor agents and agents antivirals

The compounds of the invention are useful in morbid states in which the degeneration or dysfunction of opioid receptors. This can involve the use of isotopically marked versions of compounds of the invention in diagnostic techniques and applications imaging such as emission tomography positronic (PET).

The compounds of the invention are useful for the treatment of diarrhea, depression, urinary incontinence, various mental illness, cough, pulmonary edema, various disorders gastrointestinal, spinal cord injury and addiction to drugs, including the treatment of alcohol abuse, nicotine,  of opioids and other drugs, and for system disorders sympathetic nervous, for example hypertension.

The compounds of the invention are useful as a analgesic agent for use during general anesthesia and care anesthesia monitoring. Often combinations of agents with different properties to achieve a balance of effects necessary to maintain anesthetic status (for example amnesia, analgesia, muscle relaxation and sedation). Inside this combination are inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.

The compounds of the present invention in form isotopically labeled are useful as an agent of diagnosis.

It is also within the scope of the invention. the use of any of the compounds according to formula (I) above, for the manufacture of a medication for treatment of any of the conditions outlined above.

A further aspect of the invention is a method. for the treatment of a patient suffering from any of the conditions discussed above, which gives a effective amount of a compound according to formula (I) prior to a patient in need of such treatment.

The best way to carry out the invention known herein is to use the compounds according to Example 1 (compound 12) and Example 2 (compound 13). The numbering of Compounds are performed according to the numbering in the Schemes presented below.

Preparation Methods

The compounds of the present invention can be prepare as described in Scheme I below.

General procedure for the preparation of 1.4 or 1,3-guanidinomethyl-aminomethyl-xylylene

Scheme one

3

As shown in Scheme 1 above, the compounds of the formula VI can be obtained from commercially available bis-aminoxylene (compound 1).

Compound 1 becomes the derivative mono- (diBoc) -guanidinomethyl 2 using a reagent protected guanilant, such as 1-H-pyrazol-1- (N, N-bis (tert-butoxycarbonyl) carboxamidine, in an organic solvent such as THF.

The secondary amine of formula III can be generate using a reductive amination stage, in which the compound 2 is reacted with an aldehyde II in the presence of an acid, such as acetic acid, or a Lewis acid, such as ZnCl2, in a protic solvent, such as methanol or ethanol, in presence of a reducing agent such as cyanoborohydride of sodium.

The compounds of the formula V can be obtained carrying out the formation of a urea, using compound III with a chloroformate of formula IV, in a solvent, such as methylene chloride, and in the presence of a tertiary amine as base, such as triethylamine.

Finally, the compound of formula VI is can be obtained by breaking the protective group Boc with a acid, such as aqueous hydrochloric acid, or using organic acid, such as trifluoroacetic acid, in a solvent such as chloride Methylene

The invention will now be described in more detail. by means of the following Examples, which should not be interpreted as limiting in any way of the invention.

Stage 1 (to)

Preparation of 1- (diBoc) -guanidinomethyl-4-aminomethylbenzene (compound 2)

Part TO

1-H-pyrazol-1-carboxamidine was prepared according to Bematowicz et al ., J. Org. Chem. 1992. 57, p. 2497-2502, and protected with di- tert-butyl dicarbonate to give 1-H-pyrazol-1-N, N- bis (tert-butoxycarbonyl) carboxamidine (compound 1) according to Drake et al ., Synth. , 1994, p. 579-582.

Part B

To a solution of p -xilylenediamine (compound 1) (30.8 g, 0.226 mol) in THF (300 ml) was added a solution of 1-H-pyrazol-1- (N, N- bis (tert-butoxycarbonyl) -carboxamidine (35.0 g, 0.113 mol) in THF (100 ml) The solution was stirred at room temperature for 3 h.The solvent was removed under reduced pressure, water was added to the residue, and the aqueous mixture was extracted with ethyl acetate The organic layer was washed with brine, dried over MgSO4 and concentrated.The product (compound 2) was purified by column chromatography on silica gel, using a mixture of methylene chloride as eluent: methanol, to give 24.3 g (57% yield) of 1- (diBoc) -guanidinomethyl-4-aminomethylbenzene (compound 2 in which NH2 is in position 4).

1H NMR (CDCl3) δ 8.5 (broad s, 1H), 7.32 (s, 4H), 4.65 (d, 2H), 3.89 (s, 2H), 1.5 (s, 9H), 1.48 (s, 9H).

Stage 1 (b)

Preparation of 1- (diBoc) -guanidinomethyl-3-aminomethylbenzene

1- (diBoc) -guanidinomethyl-3-aminomethylbenzene was similarly prepared from m -xylylenediamine and 1-H-pyrazol-1-N, N- bis (tert-butoxycarbonyl) carboxamidine.

1H NMR (CDCl3) δ 8.52 (broad s, 1H), 7.28-7.08 (m, 4H), 4.56 (d, 2H), 3.81 (s, 2H), 1.42 (s, 9H), 1.39 (s, 9H).

Stage 2

Reductive amination: Preparation of 1- (diBoc) -guanidinomethyl-4- [N- (cyclohexylmethyl)] benzene (compound 2 in which NH2 is in position 3)

Zinc chloride (122.79 mg, 0.90 was added mmol) and sodium cyanoborohydride (67.93 mg, 1.08 mmol) at one methanolic solution (15 ml) of compound 2 (in which the group amino is in position 4) (341 mg, 0.90 mmol) and cyclohexanecarboxaldehyde (111.17 mg, 0.99 mmol). The mixture is stirred overnight in nitrogen, then the mixture was diluted with saturated aqueous sodium bicarbonate, and extracted with methylene The organic phase was washed with brine, dried over MgSO4 and concentrated. This crude product was purified additionally by silica gel chromatography, using as solvent CH2Cl2 / MeOH (95: 5), to give 164 mg of pure desired product (compound 2 in which NH2 is in the position 3).

1H NMR (CDCl3) δ (ppm) 0.83 (2H, m, cyclohexane ring), 1.10 (3H, m, cyclohexane ring), 1.42 (9H, s, boc), 1.46 (9H, s, boc), 1.65 (6H, m, cyclohexane ring), 2.41 (2H, d, J = 6.8 Hz, C 6 H 11 -C H 2), 3.72 (2H, s, C 6 H 4 -C H 2), 4.54 (2H, d, J = 5.6 Hz, NNCNH-C H 2 -C 6 H 4), 7.18-7.25 (4H, m, Ar), 8.50 (1H, br, N H -CNN) ppm.

In Table 1, below, they are provided specific examples illustrating the preparation of amines secondary, that is, intermediates of the formula (III).

TABLE 1

4

TABLE 1 (continued)

5

TABLE 1 (continued)

6

TABLE 1 (continued)

7

TABLE 1 (continued)

8

       \ newpage
    

Scheme 2

9

As an alternative, as shown in the Scheme 2, the compounds of the formula (XI) can be obtained using compounds of the formula (VIII), in which X = CN and Y = CHO, as Starting material.

A reductive amination, which uses an amine primary with compound (VIII), in the presence of an acid such as acetic acid, and in the presence of a reducing agent such as sodium cyanoborohydride, in a solvent such as methanol or ethanol, provides a compound of the formula (IX).

The compounds of the formula (X) can be obtain by carrying out a urea reaction using compounds of the formula (IX) with a chloroformate of the formula (V), in a solvent such as methylene chloride and in the presence of an amine tertiary as base, such as triethylamine.

The compounds of the formula (XI) can be prepare by reducing the nitrile function in the formula (X), using a reducing agent such as the borane complex with THF. in a solvent such as THF.

The compounds of the formula (XV) can be prepare by reacting compounds of the formula (VIII), in the that X = CH2 Br and Y = CN, with an amine, in such a solvent as acetonitrile, providing a compound of the formula (XII). A reduction of nitrile function, using such a reducing agent as the borane complex with THF, in a solvent such as THF, provides the primary amine of the formula (XIII).

A reductive amination stage of (XIII), such as described above, provides a compound of the formula (XIV). Finally, urea formation of the secondary amine (XIV), as described above, provides a compound of the formula (XV).

Alternatively, the compounds of the formula (XV) can be prepared using a monoprotected dialdehyde, such as a compound of the formula (VIII) in which X = CH (OEt) 2 and Y = CHO, and a reductive amination, in presence of a reducing agent, such as cyanoborohydride of sodium, in a solvent such as methanol or ethanol. The formation of urea, as described above, provides a compound of the formula (XVII). Hydrolysis of diethyl acetal function in the compound (XVII), using an acid such as TFA, in a solvent such as methylene chloride, provides the aldehyde corresponding (XVIII).

Finally, a reductive amination as described above provides compounds of the formula (XV).

The invention will now be described in more detail. by the following Examples, which should not be interpreted as Limitations of the invention.

Example 1 Preparation of 1-N- (cyclohexylmethyl) -N- (N-methyl-N-phenylcarbamoyl) -aminomethyl-4-guanidinomethylbenzene (compound 12)

Compound 12 of the present Example was prepared by the following synthetic route described in Scheme 2 a continuation.

Scheme 2

       \ vskip1.000000 \ baselineskip
    

10

eleven

To a solution of compound 3 (164 mg, 0.35 mmol) in methylene chloride (10 ml) was added N-methyl-N-phenylcarbamoyl (120.78 mg, 0.71 mmol) and triethylamine (71.90 mg, 0.71 mmol). The The mixture was stirred at room temperature for 3 h, washed with a saturated aqueous NH4Cl solution and with brine, dried over MgSO4 and concentrated to give the crude product (compound 11). This crude product was used directly without purification for the preparation of compound 12. It was dissolved in dry methylene chloride (3 ml), 1.5 ml of TFA was added, and the Reaction mixture was stirred at room temperature for 1 hour. The excess solvent and TFA were evaporated, the residue was purified by preparative reverse phase HPLC to give the product desired pure (100 mg, 71% in 2 stages).

1H NMR (CDCl3) δ (ppm) 0.70 (2H, m, cyclohexane ring), 1.10 (3H, m, cyclohexane ring), 1.41 (3H, m, cyclohexane ring ), 1.53 (3H, m, cyclohexane ring), 2.72 (2H, d, J = 6.4 Hz, C 6 H 7 -C H 2), 3.00 (3H, s, NC H 3), 4.13 (2H, s, C 6 H 4 -C H 2), 4.24 (2H, d, J = 4, 8 Hz, NH-C H2 -Ph), 6.93-7.25 (9H, m, Ar), 8.13 (1H, br, N H -C = N).

MS observed (CI) : 408.45 (MH +).

The following specific compounds are prepared following the synthetic description described previously.

Examples 2-7

The following compounds were prepared using the same procedure as described in Example 1, but using the intermediate and acid chloride indicated in Table 2 a continuation.

TABLE 2

12

TABLE 2 (continued)

13

TABLE 2 (continued)

14

TABLE 2 (continued)

fifteen

TABLE 2 (continued)

17

Example 10 Preparation of 1-N - [(2,4-dichlorobenzyl) -N- (N-methyl-N-phenylcarbamoyl)] - aminomethyl-4-guanidinomethylbenzene (compound 21)

18

Following the same procedure as described in Example 1, step 2, but replacing the cyclohexanecarboxaldehyde by 2,4-dichlorobenzaldehyde, the compound of the Title 21

1 H NMR (DMSO-d 6) δ 8.2 (width, 1H), 7.5-7.1 (m, 12H), 4.5 (d, 2H), 4.2 (s, 4H), 3.1 (s, 3H).

MS (APCI): 469.95 (M + H).

Example 11 Preparation of 1-N - [(4-chlorobenzyl) -N- (N-methyl-N-phenylcarbamoyl)] - aminomethyl-4-aminomethyl-benzene (compound 25)

Compound 25 of the present Example was prepared following the procedure described in Scheme 3 a continuation.

Scheme 3

19

       \ vskip1.000000 \ baselineskip
    

twenty

Stage one

Preparation of N- (4-Chlorobenzyl) -4-Cyanobenzylamine (compound 22)

To a methanolic solution (20 ml) of 4-Chlorobenzylamine (1.02 g, 7.2 mmol) is successively added ZnCl2 (0.981 g, 7.2 mmol), 4-cyanobenzaldehyde (1,007 g, 7.3 mmol) and NaCNBH 3 (0.452 g, 7.2 mmol). The reaction mixture was stirred. at room temperature (r.t.) for 2 days. It was diluted with aqueous sodium bicarbonate, and the reaction mixture was extracted with methylene chloride The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated. The product (compound 22) was purified by silica gel chromatography: 1.43 g (77%).

1H NMR (CDCl3) δ 7.45 (d, 2H), 7.28 (d, 2H), 7.10 (s, 4H), 3.68 (s, 2H), 3.58 (s, 2H).

Stage 2

Preparation of 1-N - [(4-chlorobenzyl) -N- (N-methyl-N-phenylcarbamoyl)] - aminomethyl-4-cyanobenzene (compound 24)

Chloride was added N-methyl-N-phenylcarbamoyl (compound 23) (1,039 g, 6.12 mmol) and triethylamine (0.853 ml, 6.12 mmoles) to a solution of N- (4-Chlorobenzyl) -4-Cyanobenzylamine (compound 22) (1.43 g, 5.57 mmol) in dioxane (20 ml). Mix of reaction was stirred at r.t. for 1 day, then diluted with ethyl acetate and washed with 10% HCl, with sodium bicarbonate saturated, with water, with brine, dried over MgSO4 and concentrated to give compound 24: 1.95 g (89%).

Stage 3

Preparation of 1-N - [(4-chlorobenzyl) -N- (N-methyl-N-phenylcarbamoyl)] - aminomethyl-4-aminomethyl-benzene (compound 25)

To a solution in THF (6 ml) of 1-N - [(4-chlorobenzyl) -N'N '- (methylphenyl) carbamoyl] -aminomethyl-4-cyanobenzene  (compound 24) (0.39 g, 1 mmol) a 1 M complex of BH 3 .THF (2.2 ml). The mixture was heated at 90 ° C overnight. Then 2.55 M HCl in methanol (3 ml) was added, and the mixture of reaction was heated at reflux for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated. The product (compound 25) is purified by preparative TLC using as eluent methanol / methylene chloride / ammonium hydroxide.

1H NMR (CDCl3) δ 7.20-6.84 (m, 13H), 4.00 (s, 4H), 3.70 (s, 2H), 3.05 (s, 3H), 2.05 (wide s, 2H). MS: 394 (M + H).

Example 12 Preparation of 1-N - [(4-chlorobenzyl) -N- (N-methyl-N-phenylcarbamoyl)] - aminomethyl-4- (N-pyrrolidinomethyl) benzene (compound 32)

Compound 32 of Example 11 was prepared following the procedure described in Scheme 4 a continuation.

Scheme 4

twenty-one

22

Stage one

Preparation of 4-cyano-1-N-pyrrolinomethylbenzene (compound 28)

Bromide was dissolved from 4-cyanobenzyl (compound 26) (20.0 g, 0.102 mol) in acetonitrile (100 ml), and added to a cooled solution (0 ° C) pyrrolidine (compound 27) (8.5 g, 0.12 mol) in acetonitrile The mixture was stirred at RT (room temperature) for 3 days. The reaction mixture was acidified with 4N HCl, and washed with ethyl acetate. The aqueous layer was basified with 20% sodium hydroxide and extracted with ethyl acetate. The layer Organic was concentrated to give the product (compound 28) (11.0 g, 58%) which was taken to the next stage without purification additional.

1H NMR (CDCl3) δ 7.6 (d, 2H), 8.4 (d, 2H), 3.55 (s, 2H), 2.55 (t, 2H), 1.7 (t, 2H). MS: 187 (M + H).

Stage 2

Preparation of 4-N-aminomethyl-1-N-pyrrolinomethylbenzene (compound 29)

It dissolved 4-cyanomethyl-1-N-pyrrolinomethylbenzene (compound 28) (11 g, 59 mmol) in dry THF (20 ml). This solution a 1 M solution of borane / THF complex was added (180 ml). The mixture was refluxed overnight. Dissolution it was then cooled to r.t., and a drop was added dropwise. 3N HCl solution in methanol (120 ml). The mixture was set to reflux again all night. After cooling until room temperature, the product (compound 29) fell from the solution as a white precipitate, and was collected and washed with THF: 11.6 g.

1H NMR (CDCl3) δ 8.8 (width, 1H), 7.6 (d, 2H), 7.4 (d, 2H), 4.4 (s, 2H), 4.0 (s, 2H), 3.3 (t, 2H), 3.0 (t, 21H), 2.0 (t, 4H).

MS: 191 (M + H).

Stage 3

Preparation of N- (4-Chlorobenzyl) -1- (1-N-pyrrolidinomethyl) -benzylamine  (compound 31)

The title compound was obtained following the same procedure as described for Example 10, step 1, but replacing 4-chlorobenzylamine with the compound 29, and substituting 4-cyanobenzaldehyde for 4-chlorobenzaldehyde.

MS: 357 (M + H).

Stage 4

Preparation of 1-N - [(4-chlorobenzyl) -N- (N-methyl-N-phenylcarbamoyl)] - aminomethyl-4- (1-N-pyrrolidinomethyl) benzene (compound 32)

The title compound was obtained following the procedure described in Example 10, step 2, but substituting compound 22 by compound 31.

1H NMR (CDCl3) δ 7.55 (d, 2H), 7.45 (d, 2H), 7.4 (d, 2H), 7.2 (d, 2H), 7.0 (d, 2H), 6.95 (d, 2H), 4.3 (d, 4H), 4.1 (s, 2H), 3.25 (s, 3H), 3.1 (t, 4H), 2.05 (t, 4H).

MS: 448 (M + H).

Example 13 Preparation of 1-N - [(4-chlorobenzyl) -N- (N-methyl-N-phenylcarbamoyl)] - aminomethyl-4- (N, N-dimethyl) aminomethyl-ben-ceno (compound 35)

Compound 35 of Example 12 was prepared following the procedure described in Scheme 5 a continuation.

Scheme 5

2. 3

Stage one

Preparation of 1-N- (4-chlorobenzyl) -4- (N, N-dimethyl) -aminomethylbenzylamine (compound 34)

A round bottom flask was loaded with hydrochloride 1-N-aminomethyl-4-N, N-dimethylaminomethylbenzene (compound 33) (2.36 g, 10 mmol), 4-Chlorobenzaldehyde (compound 30) (1.51 g, 11 mmol, 97% purity), and methanol (40 ml). The mixture was stirred at r.t. for 20 minutes, then solid NaCNBH3 was added, and The reaction mixture was stirred at r.t. all night. It was diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The Combined organic extracts were washed with brine, dried over MgSO4 and concentrated, to give 1.29 g of (compound 34) as an oily residue.

Stage 2

Preparation of 1-N - [(4-chlorobenzyl) -N- (N-methyl-N-phenylcarbamoyl)] - aminomethyl-4- (N, N-dimethyl) aminomethyl-benzene (compound 35)

At a dissolution of 1-N- (4-chlorobenzyl) -4- (N, N-dimethyl) aminomethylbenzylamine (compound 34) (0.562 g, 1.95 mmol) in dioxane (8 ml) was added triethylamine (0.326 ml, 2.34 mmol) and chloride N-methyl-N-phenylcarbamoyl (compound 23) (0.395 g, 2.34 mmol). The mixture was stirred at r.t. overnight, then diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic extracts were washed with brine, dried over MgSO4 and concentrated to A colorless oil. The product (compound 35) was purified by silica gel chromatography, using methanol / acetate as eluent of ethyl / ammonium hydroxide.

1H NMR (CDCl3) δ 7.40-6.95 (m, 13H), 4.20 (s, 4H), 3.42 (s, 2H), 3.25 (s, 3H), 2.32 (s, 6H).

MS: 422 (M + H).

Example 14 Preparation of 1-N - [(4-chlorobenzyl) -N- (N-methyl-N-phenylcarbamoyl)] - aminomethyl-4- (N-methyl) aminomethyl-benzene (compound 40)

Compound 40 of Example 13 was prepared following the procedure described in Scheme 6 a continuation.

Scheme 6

24

Stage one

1-acetal preparation diethyl-4-N- (4-chlorobenzyl) benzylamine (compound 37)

Solid NaCNBH 3 was added to a solution of mono- (diethyl acetal) of terephthalaldehyde (compound 36) (0.416 g, 2 mmol) and 4-chlorobenzylamine (compound 21) (0.283 g, 2 mmol) in methanol (5 ml , which contains 1% glacial acetic acid v / v). The reaction mixture was stirred at rt overnight. It was diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated to an oil (compound 37): 61 g (91%). MS: 334.02 (M + H).

Stage 2

Preparation of 1-N - [(4-chlorobenzyl) -N- (N-methyl-N-phenylcarbamoyl)] - aminomethyl-4-carboxaldehyde (compound 39)

To a solution of 1-acetal diethyl-4-N- (4-chlorobenzyl) benzylamine (compound 37) (0.60 g, 1.8 mmol) in dioxane (5 ml) was added triethylamine (0.299 ml, 2 mmol) and chloride N-methyl-N-phenylcarbamoyl (compound 23) (0.336 g, 1.98 mmol). The mixture was stirred at r.t. overnight, then diluted with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic extracts were washed with brine, dried over MgSO4 and concentrated to give the (compound 38): 0.69 g.

The acetal (compound 38) (0.67 g, 1.42 mmol) is dissolved in 50% trifluoroacetic acid in methylene chloride (5 ml), and stirred at r.t. for 3.5 h. The mixture was concentrated until an oily residue that was redissolved in CH2Cl2 and washed with sodium bicarbonate, with brine, dried over MgSO4 and concentrated to an oil, (compound 39): 0.504 g.

1H NMR (CDCl3) δ 9.80 (s, 1H), 7.72-6.68 (m, 13H), 4.10 (s, 2H), 3.97 (s, 2H), 3.10 (s, 3H).

Stage 3

Preparation of 1-N - [(4-chlorobenzyl) -N- (N-methyl-N-phenylcarbamoyl)] - aminomethyl-4- (N-methyl) aminomethyl-benzene (compound 40)

To a methanolic solution (5 ml) of compound 39 (0.50 g, 1.28 mmol) a 2M methylamine solution was added in methanol (0.7 ml, 1.40 mmol) and glacial acetic acid (0.05 ml). Then solid NaCNBH 3 (0.08 g, 1.28 mmol) was added, and the mixture was stirred at r.t. all night. It was diluted with bicarbonate aqueous sodium, and extracted with ethyl acetate. Extracts The organics were washed with brine, dried and concentrated. He product (compound 40) was purified by gel chromatography of silica, using a mixture of methanol / chloride as eluent methylene / ammonium hydroxide.

1H NMR (CDCl3) δ 7.40-6.95 (m, 13H), 4.19 (s, 2H), 4.16 (s, 2H), 3.82 (s, 2H), 3.19 (s, 3H), 2.46 (s, 3H).

MS: 408.03 (M + H).

Pharmaceutical Compositions

The new compounds according to the present invention can be administered orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection in the joints

A preferred route of administration is oral, intravenous or intramuscular.

The dose will depend on the route of administration, of the severity of the disease, the age and weight of the patient, and other factors normally considered by the doctor when determining the individual regimen and the amount of most appropriate dosage for a particular patient.

To prepare the pharmaceutical compositions a from the compounds of this invention, inert vehicles, Pharmaceutically acceptable, they can be solid or liquid. The Solid form preparations include powders, tablets, dispersible granules, capsules, seals, and suppositories.

A solid vehicle can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be a material encapsulant

In powders, the vehicle is a finely solid divided which is in a mixture with the finely active component divided. In tablets, the active component is mixed in the Proper proportions with the vehicle, which has the properties necessary binders, and compacted in the shape and size desired

To prepare compositions in the form of suppositories, first a low point wax melts fusion, such as a mixture of fatty acid glycerides and cocoa butter, and the active ingredient is dispersed in it, by example, by agitation. The homogeneous molten mixture is poured then in molds of convenient sizes, and allowed to cool and solidify.

Suitable vehicles are carbonate of magnesium, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, gum tragacanth, methylcellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like.

Pharmaceutically acceptable salts are acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium acetate, camsilate, carbonate, chloride, citrate, dihydrochloride, edetate, edisilate, stolate, silate, fumarate, glucaptate, gluconate, glutamate, glycolylarsanylate, resorcinate hexyl, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,  iodide isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, sulfate of methyl, mucate, napsilate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, trietyoduro, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

Preferred pharmaceutically acceptable salts they are hydrochlorides, trifluoroacetates and bitrartrates.

The term composition is intended to include the active component formulation with encapsulating material as vehicle that provides a capsule in which the active component (with or without other vehicles) is surrounded by a vehicle that This mode is in association with it. Similarly, it They include stamps.

As solid, suitable dosage forms For oral administration, tablets, powders, Seals and capsules.

Compositions in liquid form include solutions, suspensions and emulsions. As an example of liquid preparations, suitable for administration parenteral, solutions of sterile water, or of water with propylene glycol, of the active compounds. The liquid compositions can also be formulated in solution in an aqueous solution of polyethylene glycol.

Aqueous solutions for administration Oral can be prepared by dissolving the active component in water, and adding dyes, flavoring agents, stabilizers, and suitable thickening agents, as desired. Suspensions aqueous for oral use can be obtained by dispersing in water the active component, finely divided, together with a material viscous, such as natural and synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other agents of suspension known in the art of formulation Pharmaceutical

Preferably, the pharmaceutical compositions They are in unit dosage form. In such a way, the composition is divided into unit doses containing quantities appropriate active component. The unit dosage form it can be a packaged preparation, containing the container discrete amounts of the preparations, for example, tablets packaged, capsules, and powders in vials or ampoules. The way of Unit dosage can also be a capsule, seal, or properly compressed, or it can be the appropriate number of Any of these packaged forms.

Biological evaluation A) In vitro model Cell culture

Human 293S cells, which express receptors \ mu, \ delta and \ kappa cloned human and resistance to neomycin, were grown in suspension at 37 ° C and 5% CO2 in shaker flasks containing calcium free DMEM, 10% of FBS, 5% BCS, 0.1% Pluronic F-68, and 600 ug / ml of geneticin.

Membrane Preparation

The cells were pelleted and resuspended in lysis buffer (50 mM Tris, pH 7.0, 2.5 mM EDTA, with PMSF added just before use up to 0.1 mM from a solution 0.1 M mother in ethanol), incubated on ice for 15 minutes, and They were then homogenized with a Polytron for 30 seconds. The suspension was rotated at 1000 g (max) for 10 minutes at 4 ° C. The supernatant was preserved on ice, and the pellets were They resuspended and spun as before. Supernatants from both centrifuges were combined and made turn at 46,000 g (max) for 30 minutes. The pellets are resuspended in cold Tris buffer (50 mM Tris / Cl, pH 7.0), and They spun again. The final pellets were resuspended in membrane buffer (50 mM Tris, 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in tubes were frozen in dry ice / ethanol of polypropylene, and stored at -70 ° C until use. The protein concentrations were determined by an assay of Lowry modified with SDS.

Binding tests

The membranes were thawed at 37 ° C, they were chilled on ice, were passed 3 times through a needle 25 gauge, and diluted in binding buffer (50 mM Tris, 3 mM MgCl2, 1 mg / ml BSA (Sigma A-7888), pH 7.4, which was stored at 4 ° C after filtration through a 0.22 m filter, and to which 5 µg / ml of freshly added aprotinin, 10 µM bestatin, 10 µM diprotin A, and nothing from DTT). 100 µl aliquots were added (per \ mug di protein, see Table 1) to 12 x 75 mm polypropylene tubes, cooled with ice, containing 100 µL of radioligand appropriate (see Table 1) and 100 µl of test compound a various concentrations. Total binding (TB) and non-specific binding (NS), in the absence and in the presence of 10 µM of naloxone, respectively. The tubes were spirally spun and they were incubated at 25 ° C for 60-75 minutes, then of which the contents were quickly filtered under vacuum and washed with about 12 ml / wash buffer tube (50 mM of Tris, pH 7.0, 3 mM MgCl2), cooled with ice, through GF / B (Whatman) filters previously soaked for at least 2 hours in 0.1% polyethyleneimine. Radioactivity (dpm) retained in the filters were measured with a beta counter after soaking the filters for at least 12 hours in minivials containing 6-7 ml of fluid for scintillation counting. If he Assay is performed in 96-well deep well plates, the filtration is done on unifiltros soaked with PEI of 96 wells, which were washed with 3 x 1 ml of wash buffer, and were dried in an oven at 55 ° C for 2 h. The filter plates are counted in a TopCount (Packard) after adding 50 \ mul of MS-20 fluid for counting by scintillation / well.

Data analysis

Specific binding (SB) was calculated as TB-NS, and SB in the presence of various compounds The test was expressed as a percentage of SB of the control. The values of IC_ {50} and the Hill coefficient (n_ {H}) for ligands that shift a specifically bound radioligand were calculated to from logit graphs or curve adjustment programs such as Ligand, GraphPad Prism, Sigma-Plot, or ReceiverFit. The values of K_ {i} were calculated from the equation of Cheng-Prussoff. Mean values ± S.E.M. of IC 50, K i and n H, were given for ligands tested in at least three displacement curves.

Receiver Saturation Experiments

The K δ values of the radioligand are determined by conducting membrane binding assays cell phones with appropriate radioligands at concentrations that range from 0.2 to 5 times the estimated K δ (up to 10 times if amounts of radioligand required are feasible). The Union Specific radioligand was expressed as pmoles / mg protein Membranic The values of K {delta} and B_ {max} from individual experiments were obtained from nonlinear adjustments of specifically bound radioligand (B) versus radioligand nM free (F) of individuals according to a site model.

B) Biological model ( in vivo model) Freund's complete adjuvant (FCA), and induced mechanoalodynia by clamping of the sciatic nerve in rats Animals

Male rats were used Sprague-Dawley (Charles River, St-Constant, Canada) weighing 175-200 g at the time of surgery. They stayed in groups of three in rooms kept thermostatically at 20ºC with a light / dark cycle of 12:12 h, and with free access to food and water. After arrival, the animals were allowed to acclimatize for at least 2 days before surgery. The experiments were approved by the appropriate ethical committee to animal studies

Experimental procedure Freund's complete adjuvant

The rats were first anesthetized in a Halothane chamber, after which they were injected s.c. 10 mul FCA in the dorsal region of the left leg, between the second and third external digit. Then the animals were allowed They will recover from anesthesia under observation in their cage.

Impingement of the sciatic nerve

Animals were prepared according to the method described by Mosconi and Kruger (1996). The rats were anesthetized with a mixture of Ketamine / Xylazine i.p. (2 ml / kg), and were placed on his right side and an incision was made over and along of the axis of the outer face of the left femur. The muscles of upper quadriceps separated to reveal the sciatic nerve on which a plastic bracelet (pipe) was placed around PE-60, 2 mm long). The wound closed then in two layers with wax and vicrile sutures 3-0

Determination of mechanodynia using the Von assay Frey

The test was performed between 08:00 and 16:00 using the method described by Chaplan et al . (1994). The rats were placed in Plexiglas cages on a wire mesh bottom that allowed access to the leg, and the rats were allowed to habituate for 10-15 minutes. The area analyzed was the left hind leg in the central part of the plant, avoiding the less sensitive pads of the leg. The leg was touched with a series of 8 Von Frey bristles with logarithmically increasing stiffness (0.41, 0.69, 1.20, 2.04, 3.63, 5.50, 8.51 and 15.14 grams ; Stoelting, Ill, USA). Von Frey bristle was applied below the mesh floor, perpendicular to the surface of the plant, with sufficient force to cause a slight buckling against the leg, and was maintained for approximately 6-8 seconds. A positive response was noted if the leg was withdrawn abruptly. The retraction immediately after the removal of the sow was also considered as a positive response. The walk was considered an ambiguous response, and in such cases the stimulus was repeated.

Test protocol

The animals were analyzed on day 1 after operation for the group treated with FCA, and on day 7 after the operation for the sciatic nerve impingement group. Be determined the 50% withdrawal threshold using the method toward up and down Dixon (1980). The trial began with the 2.04 g bristle, in the middle of the series. The stimuli are always presented consecutively, both ascending and falling. In the absence of a leg withdrawal response to the initially selected sow, one more stimulus was presented strong; in the case of the removal of the leg, the weaker following stimulus. The optimal calculation of the threshold by This method requires 6 responses in the immediate proximity of the 50% threshold, and the count of these 6 responses began when the first change in the response occurred, for example the threshold for the first time. In cases where the thresholds fell outside the range of stimuli, were assigned respectively the values of 15.14 (normal sensitivity) or 0.41 (maximally allodynic). The resulting pattern of responses positive and negative was tabulated using the convention: X = without withdrawal; O = withdrawal, and the 50% withdrawal threshold is interpolated using the formula:

g threshold of 50% = 10 ^ (Xf \ + \ k δ)} / 10,000

in which Xf = value of the last Von Frey sow used (logarithmic units); k = tabular value (from Chaplan et al . (1994)) for the positive / negative response pattern; and δ = mean difference between stimuli (logarithmic units). Here δ = 0.224.

Von Frey thresholds were converted into percentages of maximum possible effect (% MPE), according to Chaplan et al . 1994. To calculate the% MPE, the following equation was used:

% MPE = \ frac {\ text {Drug treated threshold (g) - allodynia threshold (g)}} {\ text {Control threshold (g) - allodynia threshold (g)}} x 100

Administration of test substance

The rats were injected (subcutaneously, intraperitoneally, or orally) with a test substance before Von Frey's essay, depending on the time between administration of the test compound and the Von Frey test of The nature of the test compound.

Claims (15)

1. A compound of formula I 25 in the that: m = n = 1 R1 is selected from

(i)

a linear or branched C 1 -C 6 alkyl; and

(ii)

hydrogen;

R2 is selected from

(i)

methyl; or

(ii)

phenyl optionally substituted with 1 or 2 substituents Y, in which Y is as defined more down;

R3 is selected from

(i)

-CH2 -phenyl optionally substituted with 1 or 2 substituents Y, in which Y is as defined below;

(ii)

-CH2 -cyclohexyl;

R 4 is selected from

(i)

hydrogen; or

(ii)

methyl;

R 5 is selected from

(i)

hydrogen;

(ii)

methyl; or

(iii)

26 or R 4 and R 5 together form a ring heterocyclic, optionally substituted with 1 or 2 Y substituents, in which Y is selected individually and independently of any of hydrogen, CH 3, - (CH2) p1 CF3, halogen, alkoxy C 1 -C 3, hydroxy, -NO 2, -OCF 3, -CONR a R b, -COOR a, -COR a, - (CH 2) p 2 NR a R b, - (CH 2) p 3 CH 3, - (CH 2) p 5 SO 2 R a, (alkylcycloalkyl) C 4 -C 8 in which alkyl has C 1 -C 2 and the cycloalkyl is cycloalkyl C 3 -C 6; and in those R a and R b are selected individually and regardless of hydrogen, an alkyl C 1 -C 6 branched or linear, alkenyl C 1 -C 6, cycloalkyl C 3 -C 8, and in which p 1, p 2, p3, p4, p5 and p6 is each and independently 0, 1 or 2, as well as their pharmaceutically acceptable salts. 2. A compound according to claim 1, compound which is any one selected from 27

         \ vskip1.000000 \ baselineskip
      

28

         \ vskip1.000000 \ baselineskip
      

29 30

         \ vskip1.000000 \ baselineskip
      

31

         \ vskip1.000000 \ baselineskip
      

32 33 3. 4 3. A compound according to any of the preceding claims, in the form of their hydrochloride salts, sulfate, tartrate or citrate. 4. A compound according to any of the claims 1-2 for use in therapy. 5. A compound according to claim 4, in the That therapy is the treatment of pain. 6. A compound according to claim 4, in the That therapy targets digestive disorders. 7. A compound according to claim 4, in the The therapy is aimed at spinal cord injuries. 8. A compound according to claim 4, in the that therapy targets nervous system disorders sympathetic. 9. Use of a compound according to claim 1, for the manufacture of a medicament for use in the treatment of pain. 10. Use of a compound according to claim 1, for the manufacture of a medicament for use in treatment of digestive disorders 11. Use of a compound according to claim 1, for the manufacture of a medicament for use in treatment of spinal cord injuries. 12. A compound according to claims 1-8, further characterized in that it is isotopically labeled. 13. A diagnostic agent comprising a compound of claim 1. 14. A pharmaceutical composition comprising a compound of claim 1, as an active ingredient, together with a pharmacologically and pharmaceutically acceptable vehicle. 15. A procedure for the preparation of a compound of claim 1, wherein TO)

(i)

a bis-aminoxylene of the formula

35

becomes mono- (diBoc) -guanidinomethyl of the formula (II)

36

that later reacts with an aldehyde, providing a secondary amine of the general formula IV

         \ vskip1.000000 \ baselineskip
      

37

in which R 3 is as defined in claim 1;

(ii)

he compound IV undergoes urea formation, providing a compound of the formula (VI)

         \ vskip1.000000 \ baselineskip
      

38

finally is deprotected, providing a compound of the general formula VII

39

in the that

R 1, R 2 and R 3 are as defined in claim 1; or

B)

(i)

a compound of the formula (VIII)

40

in which X is CN and Y is CHO, undergoes reductive tuning using an amine primary R3 NH2, in which R3 is as defined in the claim 1, providing a compound of the formula (IX)

41

in which R 3 is as defined in claim 1, which is then undergo a urea reaction using a chloroformate of formula (V)

42

finally is reduced, providing a compound of formula (XI)

43

or

(ii)

he compound (VIII), in which X is CH 2 Br and Y is CN, is made reacting with an amine R 4 R 5 NH in which R 4 and R 5 are as defined in claim 1, providing a compound of the formula (XII)

44

which is reduced and it is reacted with an aldehyde R 3 CHO, in which R 3 is as defined in formula I of claim 1, and finally undergo a reaction of urea with a chloroformate (V), as in step (i), providing a compound of the formula (XV)

Four. Five

in which R1, R2, R3, R4 and R5 are as defined in claim 1